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贝拉西普——抗排斥反应战场上的新武器

孙赫 孙旖旎 程颖

孙赫, 孙旖旎, 程颖. 贝拉西普——抗排斥反应战场上的新武器[J]. 器官移植, 2021, 12(3): 280-287. doi: 10.3969/j.issn.1674-7445.2021.03.005
引用本文: 孙赫, 孙旖旎, 程颖. 贝拉西普——抗排斥反应战场上的新武器[J]. 器官移植, 2021, 12(3): 280-287. doi: 10.3969/j.issn.1674-7445.2021.03.005
Sun He, Sun Yini, Cheng Ying. Belatacept: a new weapon in anti-rejection battlefield[J]. ORGAN TRANSPLANTATION, 2021, 12(3): 280-287. doi: 10.3969/j.issn.1674-7445.2021.03.005
Citation: Sun He, Sun Yini, Cheng Ying. Belatacept: a new weapon in anti-rejection battlefield[J]. ORGAN TRANSPLANTATION, 2021, 12(3): 280-287. doi: 10.3969/j.issn.1674-7445.2021.03.005

贝拉西普——抗排斥反应战场上的新武器

doi: 10.3969/j.issn.1674-7445.2021.03.005
基金项目: 

辽宁省教育厅科学研究项目(自然科学类) FWZR2020002

详细信息
    作者简介:

    孙赫,男,1986年生,博士,主治医师,研究方向为移植免疫学,Email:sunxiaohong6@163.com

    通讯作者:

    程颖,女,1975年生,博士,教授,研究方向为器官移植,Email:chengying75@sina.com

  • 中图分类号: R617, R392

Belatacept: a new weapon in anti-rejection battlefield

More Information
  • 摘要: 贝拉西普作为针对CD28受体的共刺激阻滞剂,已在欧美国家获批并应用于器官移植排斥反应的治疗。贝拉西普已被证实较钙调磷酸酶抑制剂(CNI)可更好地提高受者及移植物的长期存活率,并改善移植物功能,但同时也存在排斥反应发生率较高的问题。鉴于此,移植工作者尝试优化贝拉西普免疫抑制方案,并取得了较好的临床疗效。诚然,贝拉西普已被证实对于记忆性T细胞的作用欠佳,但因其特异性针对免疫细胞及不良反应小的特点,在探索新的共刺激分子靶点以优化免疫抑制方案上仍具有潜在价值。本文从共刺激阻滞剂的问世、贝拉西普的临床疗效及临床应用、引起贝拉西普耐药性排斥反应的“元凶”等方面进行综述。

     

  • [1] Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients[J]. Am J Transplant, 2009, 9(Suppl 3): S1-S155. DOI: 10.1111/j.1600-6143.2009.02834.x.
    [2] HART A, SMITH JM, SKEANS MA, et al. OPTN/SRTR 2015 Annual Data Report: Kidney[J]. Am J Transplant, 2017, 17(Suppl 1): 21-116. DOI: 10.1111/ajt.14124.
    [3] MEIER-KRIESCHE HU, SCHOLD JD, SRINIVAS TR, et al. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era[J]. Am J Transplant, 2004, 4(3): 378-383. DOI: 10.1111/j.1600-6143.2004.00332.x.
    [4] HAMRAHIAN SM, FÜLÖP T. Hyperkalemia and hypertension post organ transplantation - a management challenge[J]. Am J Med Sci, 2021, 361(1): 106-110. DOI: 10.1016/j.amjms.2020.06.021.
    [5] GUETA I, MARKOVITS N, YARDEN-BILAVSKY H, et al. High tacrolimus trough level variability is associated with rejections after heart transplant[J]. Am J Transplant, 2018, 18(10): 2571-2578. DOI: 10.1111/ajt.15016.
    [6] JENNINGS DL, BOHN B, ZUVER A, et al. Gut microbial diversity, inflammation, and oxidative stress are associated with tacrolimus dosing requirements early after heart transplantation[J]. PLoS One, 2020, 15(5): e0233646. DOI: 10.1371/journal.pone.0233646.
    [7] CASTEDAL M, SKOGLUND C, AXELSON C, et al. Steroid-free immunosuppression with low-dose tacrolimus is safe and significantly reduces the incidence of new-onset diabetes mellitus following liver transplantation[J]. Scand J Gastroenterol, 2018, 53(6): 741-747. DOI: 10.1080/00365521.2018.1463390.
    [8] SHRESTHA BM. Two decades of tacrolimus in renal transplant: basic science and clinical evidences[J]. Exp Clin Transplant, 2017, 15(1): 1-9. DOI: 10.6002/ect.2016.0157.
    [9] JOUVE T, NOBLE J, ROSTAING L, et al. An update on the safety of tacrolimus in kidney transplant recipients, with a focus on tacrolimus minimization[J]. Expert Opin Drug Saf, 2019, 18(4): 285-294. DOI: 10.1080/14740338.2019.1599858.
    [10] OBERBAUER R, BESTARD O, FURIAN L, et al. Optimization of tacrolimus in kidney transplantation: new pharmacokinetic perspectives[J]. Transplant Rev (Orlando), 2020, 34(2): 100531. DOI: 10.1016/j.trre.2020.100531.
    [11] JENKINS MK, SCHWARTZ RH. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo[J]. J Exp Med, 1987, 165(2): 302-319. DOI: 10.1084/jem.165.2.302.
    [12] SHARMA P, WAGNER K, WOLCHOK JD, et al. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps[J]. Nat Rev Cancer, 2011, 11(11): 805-812. DOI: 10.1038/nrc3153.
    [13] LARSEN CP, ELWOOD ET, ALEXANDER DZ, et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways[J]. Nature, 1996, 381(6581): 434-438. DOI: 10.1038/381434a0.
    [14] PARDOLL DM. The blockade of immune checkpoints in cancer immunotherapy[J]. Nat Rev Cancer, 2012, 12(4): 252-264. DOI: 10.1038/nrc3239.
    [15] FORD ML. T cell cosignaling molecules in transplantation[J]. Immunity, 2016, 44(5): 1020-1033. DOI: 10.1016/j.immuni.2016.04.012.
    [16] JUNE CH, LEDBETTER JA, LINSLEY PS, et al. Role of the CD28 receptor in T-cell activation[J]. Immunol Today, 1990, 11(6): 211-216. DOI: 10.1016/0167-5699(90)90085-n.
    [17] WEKERLE T. T cell subsets predicting belatacept-resistant rejection: finding the root where the trouble starts[J]. Am J Transplant, 2017, 17(9): 2235-2237. DOI: 10.1111/ajt.14390.
    [18] CASTRO-ROJAS CM, ALLOWAY RR, WOODLE ES, et al. High dimensional renal profiling: towards a better understanding or renal transplant immune suppression[J]. Curr Transplant Rep, 2019, 6(1): 60-68. DOI: 10.1007/s40472-019-0225-1.
    [19] KHAILAIE S, ROWSHANRAVAN B, ROBERT PA, et al. Characterization of CTLA4 trafficking and implications for its function[J]. Biophys J, 2018, 115(7): 1330-1343. DOI: 10.1016/j.bpj.2018.08.020.
    [20] VINCENTI F, LARSEN C, DURRBACH A, et al. Costimulation blockade with belatacept in renal transplantation[J]. N Engl J Med, 2005, 353(8): 770-781. DOI: 10.1056/NEJMoa050085.
    [21] VINCENTI F, CHARPENTIER B, VANRENTERGHEM Y, et al. A phase Ⅲ study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study)[J]. Am J Transplant, 2010, 10(3): 535-546. DOI: 10.1111/j.1600-6143.2009.03005.x.
    [22] VINCENTI F, LARSEN CP, ALBERU J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients[J]. Am J Transplant, 2012, 12(1): 210-217. DOI: 10.1111/j.1600-6143.2011.03785.x.
    [23] ROSTAING L, VINCENTI F, GRINYÓ J, et al. Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of the BENEFIT study[J]. Am J Transplant, 2013, 13(11): 2875-2883. DOI: 10.1111/ajt.12460.
    [24] VINCENTI F, ROSTAING L, GRINYO J, et al. Belatacept and long-term outcomes in kidney transplantation[J]. N Engl J Med, 2016, 374(4): 333-343. DOI: 10.1056/NEJMoa1506027.
    [25] DURRBACH A, PESTANA JM, PEARSON T, et al. A phase Ⅲ study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study)[J]. Am J Transplant, 2010, 10(3): 547-557. DOI: 10.1111/j.1600-6143.2010.03016.x.
    [26] PESTANA JO, GRINYO JM, VANRENTERGHEM Y, et al. Three-year outcomes from BENEFIT-EXT: a phase Ⅲ study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys[J] Am J Transplant, 2012, 12(3): 630-639. DOI: 10.1111/j.1600-6143.2011.03914.x.
    [27] CHARPENTIER B, MEDINA PESTANA JO, DEL C RIAL M, et al. Long-term exposure to belatacept in recipients of extended criteria donor kidneys[J]. Am J Transplant, 2013, 13(11): 2884-2891. DOI: 10.1111/ajt.12459.
    [28] DURRBACH A, PESTANA JM, FLORMAN S, et al. Long-term outcomes in belatacept- versus cyclosporine-treated recipients of extended criteria donor kidneys: final results from BENEFIT-EXT, a phase Ⅲ randomized study[J]. Am J Transplant, 2016, 16(11): 3192-3201. DOI: 10.1111/ajt.13830.
    [29] DE GRAAV GN, BAAN CC, CLAHSEN-VAN GRONINGEN MC, et al. A randomized controlled clinical trial comparing belatacept with tacrolimus after de novo kidney transplantation[J]. Transplantation, 2017, 101(10): 2571-2581. DOI: 10.1097/TP.0000000000001755.
    [30] ADAMS AB, GOLDSTEIN J, GARRETT C, et al. Belatacept combined with transient calcineurin inhibitor therapy prevents rejection and promotes improved long-term renal allograft function[J] Am J Transplant, 2017, 17(11): 2922-2936. DOI: 10.1111/ajt.14353.
    [31] BRAY RA, GEBEL HM, TOWNSEND R, et al. De novo donor-specific antibodies in belatacept-treated vs cyclosporine-treated kidney-transplant recipients: post hoc analyses of the randomized phase Ⅲ BENEFIT and BENEFIT-EXT studies[J]. Am J Transplant, 2018, 18(7): 1783-1789. DOI: 10.1111/ajt.14721.
    [32] BRAY RA, GEBEL HM, TOWNSEND R, et al. Posttransplant reduction in preexisting donor-specific antibody levels after belatacept- versus cyclosporine-based immunosuppression: post hoc analyses of BENEFIT and BENEFIT-EXT[J]. Am J Transplant, 2018, 18(7): 1774-1782. DOI: 10.1111/ajt.14738.
    [33] EVERLY MJ, ROBERTS M, TOWNSEND R, et al. Comparison of de novo IgM and IgG anti-HLA DSAs between belatacept- and calcineurin-treated patients: an analysis of the BENEFIT and BENEFIT-EXT trial cohorts[J]. Am J Transplant, 2018, 18(9): 2305-2313. DOI: 10.1111/ajt.14939.
    [34] EVERLY MJ, REBELLATO LM, HAISCH CE, et al. Impact of IgM and IgG3 anti-HLA alloantibodies in primary renal allograft recipients[J]. Transplantation, 2014, 97(5): 494-501. DOI: 10.1097/01.TP.0000441362.11232.48.
    [35] BADELL IR, LA MURAGLIA GM 2ND, LIU D, et al. Selective CD28 blockade results in superior inhibition of donor-specific T follicular helper cell and antibody responses relative to CTLA4-Ig[J]. Am J Transplant, 2018, 18(1): 89-101. DOI: 10.1111/ajt.14400.
    [36] LA MURAGLIA GM 2ND, ZENG S, CRICHTON ES, et al. Superior inhibition of alloantibody responses with selective CD28 blockade is CTLA-4 dependent and T follicular helper cell specific[J]. Am J Transplant, 2021, 21(1): 73-86. DOI: 10.1111/ajt.16004.
    [37] LEIBLER C, THIOLAT A, HÉNIQUE C, et al. Control of humoral response in renal transplantation by belatacept depends on a direct effect on B cells and impaired T follicular helper-B cell crosstalk[J]. J Am Soc Nephrol, 2018, 29(3): 1049-1062. DOI: 10.1681/ASN.2017060679.
    [38] NOBLE J, JOUVE T, JANBON B, et al. Belatacept in kidney transplantation and its limitations[J]. Expert Rev Clin Immunol, 2019, 15(4): 359-367. DOI: 10.1080/1744666X.2019.1574570.
    [39] PEREZ CP, PATEL N, MARDIS CR, et al. Belatacept in solid organ transplant: review of current literature across transplant types[J]. Transplantation, 2018, 102(9): 1440-1452. DOI: 10.1097/TP.0000000000002291.
    [40] MASSON P, HENDERSON L, CHAPMAN JR, et al. Belatacept for kidney transplant recipients[J]. Cochrane Database Syst Rev, 2014(11): CD010699. DOI: 10.1002/14651858.CD010699.pub2.
    [41] ROSTAING L, MASSARI P, GARCIA VD, et al. Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase Ⅱ study[J]. Clin J Am Soc Nephrol, 2011, 6(2): 430-439. DOI: 10.2215/CJN.05840710.
    [42] GRINYO J, ALBERU J, CONTIERI FL, et al. Improvement in renal function in kidney transplant recipients switched from cyclosporine or tacrolimus to belatacept: 2-year results from the long-term extension of a phase Ⅱ study[J]. Transpl Int, 2012, 25(10): 1059-1064. DOI: 10.1111/j.1432-2277.2012.01535.x.
    [43] GRINYÓ JM, DEL CARMEN RIAL M, ALBERU J, et al. Safety and efficacy outcomes 3 years after switching to belatacept from a calcineurin inhibitor in kidney transplant recipients: results from a phase 2 randomized trial[J]. Am J Kidney Dis, 2017, 69(5): 587-594. DOI: 10.1053/j.ajkd.2016.09.021.
    [44] MALVEZZI P, FISCHMAN C, RIGAULT G, et al. Switching renal transplant recipients to belatacept therapy: results of a real-life gradual conversion protocol[J]. Transpl Immunol, 2019, 56: 101207. DOI: 10.1016/j.trim.2019.04.002.
    [45] TERREC F, JOUVE T, NACIRI-BENNANI H, et al. Late conversion from calcineurin inhibitors to belatacept in kidney-transplant recipients has a significant beneficial impact on glycemic parameters[J]. Transplant Direct, 2019, 6(1): e517. DOI: 10.1097/TXD.0000000000000964.
    [46] BERTRAND D, TERREC F, ETIENNE I, et al. Opportunistic infections and efficacy following conversion to belatacept-based therapy after kidney transplantation: a French multicenter cohort[J]. J Clin Med, 2020, 9(11): 3479. DOI: 10.3390/jcm9113479.
    [47] KLINTMALM GB, FENG S, LAKE JR, et al. Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase Ⅱ randomized study[J]. Am J Transplant, 2014, 14(8): 1817-1827. DOI: 10.1111/ajt.12810.
    [48] LAMATTINA JC, JASON MP, HANISH SI, et al. Safety of belatacept bridging immunosuppression in hepatitis C-positive liver transplant recipients with renal dysfunction[J]. Transplantation, 2014, 97(2): 133-137. DOI: 10.1097/01.TP.0000438635.44461.2e.
    [49] SCHWARZ C, RASOUL-ROCKENSCHAUB S, SOLIMAN T, et al. Belatacept treatment for two yr after liver transplantation is not associated with operational tolerance[J]. Clin Transplant, 2015, 29(1): 85-89. DOI: 10.1111/ctr.12483.
    [50] VALLEJO AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence[J]. Immunol Rev, 2005, 205: 158-169. DOI: 10.1111/j.0105-2896.2005.00256.x.
    [51] SHABIR S, SMITH H, KAUL B, et al. Cytomegalovirus-associated CD4(+) CD28(null) cells in NKG2D-dependent glomerular endothelial injury and kidney allograft dysfunction[J]. Am J Transplant, 2016, 16(4): 1113-1128. DOI: 10.1111/ajt.13614.
    [52] MOU D, ESPINOSA JE, STEMPORA L, et al. Viral-induced CD28 loss evokes costimulation independent alloimmunity[J]. J Surg Res, 2015, 196(2): 241-246. DOI: 10.1016/j.jss.2015.02.033.
    [53] ENGELA AU, BAAN CC, LITJENS NH, et al. Mesenchymal stem cells control alloreactive CD8(+) CD28(-) T cells[J]. Clin Exp Immunol, 2013, 174(3): 449-458. DOI: 10.1111/cei.12199.
    [54] LO DJ, ANDERSON DJ, WEAVER TA, et al. Belatacept and sirolimus prolong nonhuman primate renal allograft survival without a requirement for memory T cell depletion[J]. Am J Transplant, 2013, 13(2): 320-328. DOI: 10.1111/j.1600-6143.2012.04342.x.
    [55] LO DJ, WEAVER TA, STEMPORA L, et al. Selective targeting of human alloresponsive CD8+ effector memory T cells based on CD2 expression[J]. Am J Transplant, 2011, 11(1): 22-33. DOI: 10.1111/j.1600-6143.2010.03317.x.
    [56] MATHEWS DV, WAKWE WC, KIM SC, et al. Belatacept-resistant rejection is associated with CD28+ memory CD8 T cells[J]. Am J Transplant, 2017, 17(9): 2285-2299. DOI: 10.1111/ajt.14349.
    [57] CORTES-CERISUELO M, LAURIE SJ, MATHEWS DV, et al. Increased pretransplant frequency of CD28+ CD4+ TEM predicts belatacept-resistant rejection in human renal transplant recipients[J]. Am J Transplant, 2017, 17(9): 2350-2362. DOI: 10.1111/ajt.14350.
    [58] ESPINOSA J, HERR F, THARP G, et al. CD57(+) CD4 T cells underlie belatacept-resistant allograft rejection[J]. Am J Transplant, 2016, 16(4): 1102-1112. DOI: 10.1111/ajt.13613.
    [59] KRUMMEY SM, CHEESEMAN JA, CONGER JA, et al. High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept[J]. Am J Transplant, 2014, 14(3): 607-614. DOI: 10.1111/ajt.12600.
    [60] KRUMMEY SM, FLOYD TL, LIU D, et al. Candida-elicited murine Th17 cells express high CTLA-4 compared with Th1 cells and are resistant to costimulation blockade[J]. J Immunol, 2014, 192(5): 2495-2504. DOI: 10.4049/jimmunol.1301332.
    [61] VANHOVE B, POIRIER N, SOULILLOU JP, et al. Selective costimulation blockade with antagonist anti-CD28 therapeutics in transplantation[J]. Transplantation, 2019, 103(9): 1783-1789. DOI: 10.1097/TP.0000000000002740.
    [62] SUN H, HARTIGAN CR, CHEN CW, et al. TIGIT regulates apoptosis of risky memory T cell subsets implicated in belatacept-resistant rejection[J]. Am J Transplant, 2021, DOI: 10.1111/ajt.16571[Epub ahead of print].
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出版历程
  • 收稿日期:  2021-01-11
  • 网络出版日期:  2021-05-19
  • 刊出日期:  2021-05-15

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